Preproghrelin is cleaved into at least two distinct peptides, ghrelin (1) and obestatin (2). The major source of circulating ghrelin is the stomach (1) and ghrelin plasma levels inversely correlate with feeding (3, 4). Ghrelin mRNA and ghrelin-like immunoreactivity are also found in the brain (1, 5-8), mainly in the arcuate nucleus and in the internuclear space in the hypothalamus. Ghrelin is involved in the short- and long-term regulation of energy balance by stimulating feeding and suppressing energy expenditure (reviewed in (9)). The role of obestatin in the regulation of feeding and metabolism is less clear. Several (2, 10-12) but not all (13, 14) studies showed that acute administration of obestatin suppresses food intake in rats and mice and repeated obestatin injections lead to suppressed body weight gain in mice suggesting enhanced energy expenditure (10).
Ghrelin and obestatin may also play a role in sleep regulation. Sleep deprivation induces increases in hypothalamic and plasma ghrelin levels (6), and central or systemic administration of ghrelin has a strong wake-promoting effect in rats while the injection of obestatin facilitates sleep in rats (15-17). It is posited that increased wakefulness and feeding are two parallel outputs of a hypothalamic ghrelinergic circuitry that also involve the function of neuropeptide Y-ergic and orexinergic neurons (17). Sleep-wake activity (18) and metabolism (19) of ghrelin knockout (KO) mice are, however, relatively normal if the animals are kept under thermoneutral ambient temperature with food provided ad libitum. Since there are multiple substances involved in the regulation of metabolism and sleep-wake activity, it seems likely that under normal physiological conditions, redundant regulatory systems compensate for the lack of the preproghrelin gene product(s).